Combination therapy for HIV with adenosine derivative and capsid inhibitors
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Publication Number
US-12257264-B2
Publication Date
2025-03-25
Expiration Date
Abstract
The present disclosure is directed to methods of treating or preventing RNA virus infections and retroviral diseases, such as HIV and AIDS, comprising administering to a subject in need an effective amount of (a) a capsid inhibitor and (b) an adenosine derivative disclosed herein. Compositions comprising an effective amount of an adenosine derivative and an effective amount of a capsid (CA) inhibitor are also provided.
Core Innovation
The disclosure defines adenosine-derivative structures around a Formula (1) core and a Formula 4-A compound, with substituent variables, linker-related fragments, and a halogen X. The scope includes related formulas, stereoisomers, tautomers, pharmaceutically acceptable salts, solvates, hydrates, isomers, and prodrugs, together with carbamate and carbonate prodrug-like derivatives and pharmaceutical composition embodiments.
The adenosine derivatives are described as metabolized in vivo to produce EFdA-like reverse transcriptase inhibitor activity and other antiviral activities, including conversion to a target drug in human plasma. The disclosure further describes plasma and liver S9 conversion measurements supporting conversion to EFdA, together with fluorinated purine nucleoside-like intermediates and related compounds, including intermediates containing a fluorinated purine and an ethynyl substituent.
The described structures are linked to HIV therapy and anti-HIV capsid inhibitors, with lenacapavir described as a particular capsid inhibitor. The therapy is intended for treatment and prevention of HIV infection, including HIV-1, HIV-2, AIDS, multidrug resistant HIV, NRTI-resistant strains identified by M184V and K65R, and referenced RNA virus infection, with optional PrEP use.
Example evaluation of formula 4-A with lenacapavir is described in an antiviral assessment against HIV-1 NL4-3 in MT4 cells using MacSynergy II, with synergy volume values. The document also describes simultaneous or sequential administration of the capsid inhibitor and Formula 4-A, together with example structural embodiments, named adenosine-derivative molecules, and reported characterization data.
Claims Coverage
The independent claims cover a pharmaceutical tablet containing a compound of Formula 4-A with a pharmaceutically acceptable carrier, and an orally administered regimen for treating or preventing HIV infection using the same Formula 4-A tablet. Dependent claims add an anti-HIV agent from an enumerated set that includes a capsid inhibitor, narrowed to lenacapavir, with simultaneous or sequential administration of the capsid inhibitor and Formula 4-A. Across the claim set, there are three main inventive feature groupings: the Formula 4-A tablet, the oral HIV treatment/prevention method, and the optional anti-HIV agent with capsid inhibitor timing.
Formula 4-A in a pharmaceutical tablet
A pharmaceutical tablet comprising a compound of Formula 4-A or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
Oral treating or preventing HIV infection with Formula 4-A
A method of treating or preventing an HIV infection in a subject in need thereof by orally administering an effective amount of a pharmaceutical tablet comprising a compound of Formula 4-A or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
Optional additional anti-HIV agent and capsid inhibitor selection
The tablet or method further includes an anti-HIV agent selected from a specified group that includes a capsid inhibitor.
Lenacapavir as the capsid inhibitor
The capsid inhibitor in the optional combination is lenacapavir.
Simultaneous or sequential administration of capsid inhibitor with Formula 4-A
The capsid inhibitor and the compound of Formula 4-A or a pharmaceutically acceptable salt thereof are administered simultaneously or sequentially.
Overall, the claims focus on a Formula 4-A compound formulated in a pharmaceutical tablet for oral use in treating or preventing HIV infection, optionally combined with a selected anti-HIV agent that can be a capsid inhibitor. The capsid inhibitor is narrowed specifically to lenacapavir, and the CA inhibitor is administered simultaneously or sequentially with the Formula 4-A compound.
Stated Advantages
Fast conversion of the adenosine derivatives to a target drug in human plasma, with more than 30% within 30 min as described.
Synergistic antiviral activity when an adenosine-derivative compound is combined with a capsid inhibitor, with synergy volume ranges reported.
Provides EFdA-like reverse transcriptase inhibitor activity after in vivo metabolism of the adenosine derivatives.
Provides other antiviral activities.
Supports HIV infection treatment or prevention via pharmaceutical tablet oral administration.
Documented Applications
Prevention or treatment of HIV infection in a subject in need thereof using orally administered pharmaceutical tablets comprising a compound of Formula 4-A or a pharmaceutically acceptable salt with a pharmaceutically acceptable carrier.
Use of the disclosed combinations for prevention or treatment contexts that include HIV-1, HIV-2, AIDS, NRTI-resistant HIV such as M184V and K65R, and referenced RNA virus infection.
PrEP use is referenced as an option in the document context for the disclosed compounds and approaches.
Evaluating antiviral interaction between formula 4-A and lenacapavir against HIV-1 NL4-3 in MT4 cells using MacSynergy II, with synergy and antagonism reporting.
Assessing conversion stability of adenosine-derivative prodrugs to EFdA via plasma and liver S9 conversion measurements.
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